Influenza viruses are enveloped RNA viruses that belong to the family of Orthomyxoviridae (Palese and Shaw, 2007). Influenza A and B viruses are considered to be major human pathogens and in a normal season they can cause between 3-5 million cases of severe illness and up to 500,000 deaths worldwide (World Health Organization, 2003). Influenza A viruses can also cause pandemics such as those that occurred in 1918, 1957 and 1968. These outbreaks resulted in high mortality rates because of the lack of pre-existing immunity against the new virus strain. The current pandemic outbreak, beginning in 2009, of the swine-origin H1N1 influenza virus (Wang & Palese, 2009), and the emergence of the highly pathogenic avian H5N1 influenza virus in the late 1990s (Claas et al., 1998), have sparked renewed interest in the development of anti-influenza virus drugs.
Strategies for identifying targets for antiviral intervention typically focus on compounds that attack the virus itself, i.e., viral proteins—the structural components of the virion, as well as viral genome-encoded enzymes which are necessary for propagation of the virus. The approach of targeting viral proteins has several limitations: i) the limited number of viral targets; ii) viral targets tend to be highly specific to a particular virus or even strain of virus; and iii) viruses are able to rapidly alter their genetic composition to develop resistance to antiviral drugs. Another approach in antiviral drug development is to design drugs to strengthen the host's immune system to fight the viral infection, rather than to fight the viral infection itself. Using this strategy, drugs are designed to boost the host's immune system to allow the host to better fight off infection by the virus.
Cellular targets have traditionally been considered less desirable candidates for antiviral therapy. Relatively few antiviral drugs have been directed at host enzymes for several reasons, the most prominent being the high risk of toxicity to the host itself. Although host cell factors play a key role in facilitating viral growth and propagation, strategies for attacking such host factors remain elusive.
Currently there are only four U.S. Food and Drug Administration (FDA)—approved drugs available for the treatment of influenza, amantadine, rimantadine, oseltamivir, and zanamivir (DeClercq, 2006). The adamantanes (amantadine and rimantadine) block the M2 ion channel of the virus and prevent the release of the viral genome into the host cell (Pinto and Lamb, 1995; Wharton et al., 1994). These drugs are effective if used prophylactically and if administered within 48 hours of infection but are not effective against influenza B viruses. However, the development of widespread resistance has precluded the use of adamantanes in recent influenza seasons (Bright et al., 2006) and isolates of the H5N1 influenza virus have been shown to be resistant to these drugs due to mutations in M2 (Cheung et al., 2006).
The preferred treatment for influenza virus infection is now the use of the neuraminidase (NA) inhibitors, oseltamivir and zanamivir (Garman and Laver, 2004). By targeting NA, these compounds prevent the release of the virus from the infected cell and halt the spread of the virus. As part of its pandemic preparedness plan, the World Health Organization (WHO) has advised that supplies of the NA inhibitors be stockpiled, but it is always advantageous to have at least two antiviral drugs (aimed at different targets) available due to the possible emergence of resistant virus strains. In fact the 2007-2008 influenza season in the Northern hemisphere has shown a marked increase in the number of H1N1 isolates that are resistant to oseltamivir (World Health Organization, 2008) and concerns have also been raised regarding oseltamivir-resistant H5N1 influenza viruses isolated from patients in Southeast Asia (Le et al., 2005). There is now widespread resistance to both of these drug classes (Layne et al., 2009).
Thus, a major challenge to anti-influenza drug development is finding new strategies for combating influenza virus infection.